Metallocene-based chiral phosphine or arsine ligands

Abstract

The present invention relates to metallocene-based phosphine ligands having chirality at phosphorus and at least one other element of chirality (planar chirality and/or chirality at carbon); and to the use of such ligands in asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds. A method for the preparation of ligands according to the invention involving the conversion of the ortho-lithiated substituted metallocene to a phosphine chiral at phosphorus is also disclosed.

1. A metallocene-based ligand having a formula selected from the group consisting of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), and Formula (IX): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 W is phosphorus or arsenic; 
 M is a metal; 
 R 1  and R 2  are different from each other and are independently selected from the group consisting of unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, unsubstituted heteroarylamino, substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, and substituted heteroarylamino; 
 R 3  and R 4  are independently selected from the group consisting of substituted branched-chain alkyl, substituted straight-chain alkyl, substituted cycloalkyl, substituted carbocyclic aryl, substituted heteroaryl, unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted cycloalkyl, unsubstituted carbocyclic aryl, and unsubstituted heteroaryl; 
 n is an integer from 0 to 3; 
 m is an integer from 0 to 5; 
 Q is the group 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 8  is selected from the group consisting of substituted straight-chain alkyl, substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; R 9  and R 10″  are independently selected from the group consisting of hydrogen, substituted straight-chain alkyl, substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; or 
 Q is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 6  and R 7  are independently selected from the group consisting of substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, substituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, substituted heteroarylamino, unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, and unsubstituted heteroarylamino; 
 R 8 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, substituted straight-chain alkyl, unsubstituted straight-chain alkyl, substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; R 11  is selected from the group consisting of OR 13 , SR 13 , NHR 13 , and NR 13 R 14 , wherein 
 R 13  and R 14  are independently selected from the group consisting of substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; R 12  is selected from the group consisting of hydrogen, halogen, OR 13 , SR 13 , NR 13 R 14 , substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl, and n′ is 0 to 4; 
 R 5  is selected from: 
 
       
         
           
           
               
               
           
         
         wherein R 15 , R 16  and R 17  are independently selected from the group consisting of hydrogen, halogen, OR 13 , SR 13 , NR 13 R 14 , substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; and wherein the two geminal substituents R 18  together are a doubly bonded oxygen atom, or each substituent R 18  is individually hydrogen; and G is selected from the group consisting of —C(═O)NH—R*—NHCO—, —C(═O)—OR*O—C(═O)—, —C(═O)—R*C(═O)—, —CH═N—R*—N═CH—, —CH 2 NH—R*—NHCH 2 —, —CH 2 NHC(═O)—R*—C(═O)NHCH 2 —, —CH(R 8 )NH—R*—NH(CH(R 8 )—, —CH(R 8 )NHC(═O)—R*—C(═O)NHCH(R 8 )—, —C(═O)NH—R—NHC(═O)—, —C(═O)—ORO—C(═O)—, —C(═O)—RC(═O)—, —CH═N—R—N═CH—, —CH 2 NH—R—NHCH 2 —, —CH 2 NHC(═O)—R—C(═O)NHCH 2 —, —CH(R 8 )NH—R—NH(CH(R 8 )—, —CH(R 8 )NHC(═O)—R—C(═O)NHCH(R 8 )—; 
         wherein R 8  is independently selected from the group consisting of hydrogen, substituted straight-chain alkyl, unsubstituted straight-chain alkyl, substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; 
         wherein R 13  and R 14  are independently selected from the group consisting of substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; 
         —R*— and —R— are selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R 12  is as previously defined; 
         wherein the two substituents R 19  together are —(CH 2 ) m′ — or each substitutent R 18  is independently selected from the group consisting of hydrogen, substituted branched-chain alkyl, unsubstituted branched-chain alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted carbocyclic aryl, unsubstituted carbocyclic aryl, substituted heteroaryl, and unsubstituted heteroaryl; wherein the or each heteroatom is independently selected from sulphur, nitrogen, n′ is an integer of from 0 to 4; and m′ is an integer of from 1 to 8. 
       
     
     
       2. The metallocene-based ligand of  claim 1 , which is a diastereomer having Formula (IV), Formula (V), or Formula (VI). 
     
     
       3. The metallocene-based ligand of  claim 1 , which is an enantiomer having Formula (VII), Formula (VIII), or Formula (IX). 
     
     
       4. The metallocene-based ligand of  claim 1 , wherein the metallocene-based ligand is a phosphine or arsine having chirality at W, and wherein the metallocene-based ligand has at least one additional element of chirality selected from the group consisting of chirality at carbon, and axial chirality. 
     
     
       5. The metallocene-based ligand of  claim 1 , wherein the metallocene-based ligand is a diphosphine or diarsine having chirality at W, and wherein the metallocene-based ligand has two additional elements of chirality comprising chirality at carbon, and axial chirality. 
     
     
       6. The metallocene-based ligand of  claim 1 , wherein the metallocene is ferrocene. 
     
     
       7. The metallocene-based ligand of  claim 1 , wherein W is phosphorus. 
     
     
       8. A catalyst or catalyst precursor in an asymmetric transformation reaction to generate a high enantiomeric excess of a formed compound, the catalyst or catalyst precursor comprising the metallocene-based ligand of  claim 1 . 
     
     
       9. A transition metal complex containing a transition metal coordinated to a ligand according to the metallocene-based ligand of  claim 1 . 
     
     
       10. A transition metal complex according to  claim 9 , wherein the transition metal is a Group VIb or a Group VIII metal. 
     
     
       11. A method for preparing the metallocene-based ligand of  claim 1 , comprising:
 providing a metallocene-based substrate having a chiral directing substituent on one or both rings; 
 ortho-lithiating the metallocene-based substrate; and 
 converting the ortho-lithiated metallocene-based substrate to obtain the metallocene-based ligand. 
 
     
     
       12. The method according to  claim 11 , wherein the metallocene-based ligand has Formula (I) or Formula (III), wherein the metallocene-based substrate has Formula (X′): 
       
         
           
           
               
               
           
         
       
       wherein R 3  and R 4  are independently selected from the group consisting of substituted branched-chain alkyl, substituted straight-chain alkyl, substituted cycloalkyl, substituted carbocyclic aryl, substituted heteroaryl, unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted cycloalkyl, unsubstituted carbocyclic aryl, and unsubstituted heteroaryl;
 n is an integer from 0 to 3; 
 m is an integer from 0 to 5; 
 and wherein X* is a chiral directing group, wherein the step of converting the ortho-lithiated metallocene-based substrate comprises reacting the ortho-lithiated substrate with an R 1  substituted phosphine or arsine, and with an R 2 -bearing Grignard reagent or an R 2 -organolithium compound, then converting X* to Q or G. 
 
     
     
       13. A method according to  claim 12 , wherein X* is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 R a  and R b  are independently selected from the group consisting of substituted branched-chain alkyl, substituted straight-chain alkyl, substituted cycloalkyl, substituted carbocyclic aryl, substituted heteroaryl, unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted cycloalkyl, unsubstituted carbocyclic aryl, and unsubstituted heteroaryl. 
 
     
     
       14. The method according to  claim 12 , wherein the ortho-lithiation step is conducted using at least one lithiating agent selected from the group consisting of n-butyllithium, sec-butyllithium, and tert-butyllithium. 
     
     
       15. The method according to  claim 14 , wherein the step of converting the ortho-lithiated metallocene-based substrate comprises reacting the ortho-lithiated metallocene-based substrate in situ with a dichlorophosphine of the formula R 1 PCl 2  wherein R 1  is selected from the group consisting of unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, unsubstituted heteroarylamino, substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, substituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, and substituted heteroarylamino; to yield an intermediate product, wherein the intermediate product is converted to obtain the metallocene-based ligand. 
     
     
       16. The method according to  claim 15 , further comprising reacting the intermediate product with an organometallic reagent of formula R 2 Z, wherein R 2  is selected from the group consisting of unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, unsubstituted heteroarylamino, substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, substituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, and substituted heteroarylamino;
 wherein Z is Li or MgY, and wherein Y is a halide, to obtain a phosphorus chiral compound having formula (XI′): 
 
       
         
           
           
               
               
           
         
       
       wherein the phosphorous chiral compound is converted to obtain the metallocene-based ligand. 
     
     
       17. A method for preparing a metallocene-based ligand of  claim 1 , comprising:
 providing a compound of Formula (XXXVII): 
 
       
         
           
           
               
               
           
         
       
       wherein X is an achiral directing group;
 subjecting the compound of Formula (XXXVII) to enantioselective mono-ortho-lithiation using at least one lithiating agent selected from the group consisting of n-butyllithium, sec-butyllithium, and tert-butyllithium, wherein the mono-ortho-lithiation is conducted in the presence of a homochiral tertiary amine, whereby a chiral monolithium compound is obtained; reacting the chiral monolithium compound in situ with a dichlorophosphine of the formula R 1 PCl 2  followed by reacting with an organometallic reagent of the formula R 2 Z, wherein R 1  and R 2  are different from each other and are independently selected from the group consisting of unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, unsubstituted heteroarylamino, substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, substituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, and substituted heteroarylamino; 
 wherein Z is Li or MgY, and wherein Y is a halide, to obtain a phosphorus chiral compound having Formula (XXXVIII): 
 
       
         
           
           
               
               
           
         
       
       and converting the phosphorus chiral compound having Formula (XXXVIII) to the metallocene-based ligand, wherein the metallocene-based ligand has Formula (I) or Formula (III). 
     
     
       18. The method according to  claim 17 , wherein X is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein R a  and R b  are independently selected from the group consisting of substituted branched-chain alkyl, substituted straight-chain alkyl, substituted cycloalkyl, substituted carbocyclic aryl, substituted heteroaryl, unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted cycloalkyl, unsubstituted carbocyclic aryl, and unsubstituted heteroaryl. 
     
     
       19. A method for preparing a metallocene-based ligand of  claim 1 , comprising:
 providing a compound of the Formula (XXXIX): 
 
       
         
           
           
               
               
           
         
       
       wherein X* is a chiral directing group;
 subjecting the compound of Formula (XXXIX) to bis-ortho-lithiation using at least one lithiating agent selected from the group consisting of n-butyllithium, sec-butyllithium, and tert-butyllithium, whereby a bislithium compound in situ with a dichlorophosphine of the formula R 1 PCl 2  followed by reacting with an organometallic reagent of the formula R 2 Z wherein R 1  and R 2  are different from each other and are independently selected from the group consisting of unsubstituted branched-chain alkyl, unsubstituted straight-chain alkyl, unsubstituted alkoxy, unsubstituted alkylamino, unsubstituted cycloalkyl, unsubstituted cycloalkoxy, unsubstituted cycloalkylamino, unsubstituted carbocyclic aryl, unsubstituted carbocyclic aryloxy, unsubstituted heteroaryl, unsubstituted heteroaryloxy, unsubstituted carbocyclic arylamino, unsubstituted heteroarylamino, substituted branched-chain alkyl, substituted straight-chain alkyl, substituted alkoxy, substituted alkylamino, substituted cycloalkyl, substituted cycloalkoxy, substituted cycloalkylamino, substituted carbocyclic aryl, substituted carbocyclic aryloxy, substituted heteroaryl, substituted heteroaryloxy, substituted carbocyclic arylamino, and substituted heteroarylamino; 
 wherein Z is Li or MgY, and wherein Y is a halide, to obtain a phosphorus chiral compound having Formula (XXXX): 
 
       
         
           
           
               
               
           
         
       
       and converting the phosphorous chiral compound having Formula (XXX) to the metallocene-based ligand, wherein the metallocene-based ligand has Formula (II).